Parkinson's disease (PD) is a chronic incurable disease that afflicts more than a million Americans and 10 million people worldwide. Levodopa pharmacotherapy and deep brain stimulation treat only the symptoms and their therapeutic effects wear down as the disease progresses. Exercise-enhanced neuroplasticity and induced pluripotent stem cell (iPSC) therapy have the potential to revolutionize the clinical management of PD. This proposal will use a multidisciplinary approach to reveal dysfunctional nodes of neural networks caused by PD and how this neural network can be corrected through combination of exercise and transplantation of iPSC- derived dopaminergic (DA) neurons. Evidence suggests that physical activity enhances neuroplasticity yet only transiently improves motor and cognitive functions in rodent animal models and in PD patients. We have unique national resources of nonhuman primates (NHP) and imaging facilities to study the reversibility in neural networks altered by physical activity in PD and to develop efficacious long-lasting therapeutic strategies. PD is characterized by impairment in automatic motor control involving learned motor skills, such as movements, gait and balance. Automatic movements involve the caudal sensorimotor regions of the basal ganglia and the sensorimotor cortex, which are first areas affected in PD. It has been shown that through intensive exercise a PD patient can re-learn automatic tasks and improve motor function. However the beneficial effects are transient. Early studies demonstrated that transplantation of fetal DA nigral tissue to the caudal sensorimotor region of the putamen restored movement in parkinsonian patients. Based on these premises, we hypothesize that intensive exercise will enhance iPSC-derived DA graft re-innervation of the basal ganglia and reactivate D2-mediated indirect pathway to restore automaticity and habitual motor learning. Our proposal is innovative and interdisciplinary; employs novel approaches and interventions to address new mechanisms for understanding and restoring the DA circuitry in PD. The innovation and strengths of the application reside in: 1). The use of NHP model, which amazingly replicates the cardinal symptoms of PD including rigidity, bradykinesia, akinesia, resting tremor, postural instability, sleep disturbances and cognitive impairment. It also exhibits the same side effects, such as dyskinesia, to long-term L-DOPA treatment 2). The approach we propose to identify reversible functional connectivity involved in re-learning lost motor activities and remodel brain circuitry; 3). Grafting iPSC-derived DA neurons to re-establish the innervation lost in PD with enhanced neural integration through exercise; 4). The use of multimodal functional, structural and molecular PET imaging, motor and cognitive testing and morphological analysis to identify the structural substrate involved in the neuroplasticity and functional recovery. We have assembled an interdisciplinary team of experts to achieve the project goals. Understanding the effects of exercise and iPS cell therapy in a relevant animal model of PD will have significant impact on the field and may transform the way we currently manage PD. !